Beta-4-n-pentyloxybenzoyl-beta-bromoacrylic acid

ABSTRACT

A COMPOUND OF THE FORMULA   R1,R2,R3,A-BENZENE   WHEREIN R1 IS HYDROGEN, OR ALKOXY HAVING FROM 1 TO 6 CARBON ATOMS, R2 IS HYDROGEN, OR HYDROXY OR ALKOXY HAVING FROM 1 TO 6 CARBON ATOMS, AND R3 IS ALKOXY HAVING FROM 1 TO 6 CARBON ATOMS, WITH THE PROVISO THAT WHEN R1 AND R2 ARE BOTH HYDROGEN, R3 IS ALKOXY HAVING FROM 2 TO 6 CARBON ATOMS, AND WHEREIN A IS   -CO-C(-X)=CH-COOH   AND X IN THE LAST RESIDUE BEING CHLORINE OR BROMINE HAVING CYTOSTATIC ACTIVITY. AN EXAMPLE OF THE PRODUCT IS B-4-N-PENTYLOXYBENZOYLB-BROMOACRYLIC ACID.

United States Patent 3,754,023 18-4-n-PENTYLOXYBENZOYL-B- BROMOACRYLIC ACID Miroslav Semonsky, Viktor Zikan, and Vaclav Jelinek, Prague, Czechoslovakia, assiguors to Spofa United Pharmaceutical Works, Prague, Czechoslovakia No Drawing. Original application Feb. 16, 1968, Ser. No. 705,927. Divided and this application Aug. 5, 1970, Ser. No. 61,485 Claims priority, application Czechoslovakia, June 17,

1967, 1,173/67 Intc. Cl. C07c 65/20 US. Cl. 260-521 A 1 Claim ABSTRACT OF THE DISCLOSURE A compound of the formula R; wherein R is hydrogen, or alkoxy having from 1 to 6 carbon atoms, R is hydrogen, or hydroxy or alkoxy having from 1 to 6 carbon atoms, and R is alkoxy having from 1 to 6 carbon atoms, with the proviso that when R and R are both hydrogen, R is alkoxy having from 2 to 6 carbon atoms, and wherein A is X -CO-( J=CHCOOH and X in the last residue being chlorine or bromine having cytostatic activity.

An example of the product is 18-4-n-pentyloxybenzoyl- B-bromoacrylic acid.

CROSS REFERENCES TO RELATED APPLICATIONS This application is a division of application Ser. No. 705,927 filed on Feb. 16, 1968, now abandoned, in respect of Crotonic Acid Lactones and Hydrolysis Products Thereof and Method of Making the Same.

BACKGROUND OF THE INVENTION 'y-4-methoxyphenyl-a,e-dichloro-N -crotonic acid lactone has already been described previously, and the same applies to the corresponding dibromo-compound; US. Pat. No. 3,105,850. Likewise, 8-4-methoxybenzoyl-;3-bromoacrylic acid and the corresponding chloroacrylic acid have become known in connection with a study of the possible cytostatic compounds. However, the one compound, 8-4-methoxybenzoyl-fi-bromoacrylic acid, which has been used in medical practice on a limited scale, can only be administered parenterally in the form of its sodium salt. Besides, it appeared desirable to improve the toxicity rating and the process of making the compounds of this general group.

In addition, better and more significant results regarding the cytostatic action in connection with a broad variety of tumors appeared highly desirable.

The previously known methoxybenzoyl compounds also presented problems of synthetic formation. To obtain the lactone, anisole was reacted with fl-formyl-u,fl-dichloroacrylic acid (mucochloric acid) in the presence of a reagent such as polyphosphoric acid. This process required a comparatively large amount of this acid, which is not earily made, and therefore resulted in a rather large volume of reaction mixture and a relatively poor yield and limited reproducibility. There was also the risk of decomposition both of the starting compound and the reaction product. In addition, certain derivatives could not be formed at all with polyphosphoric acid, as, for instance,

3,754,023 Patented Aug. 21, 1973 the 'y-4-hydroxy 2 methoxyphenyl-a,;8-dibromocrotonic acid lactone.

Other problems existed in the hydrolysis of the lactone to the acid, for which previously magnesium oxide or calcium carbonate had been suggested together with a water-miscible solvent such as dioxane (see US. Pat. No. 3,105,850). The use of these salts, such as the magnesium salt, affects the stability of the materials during the course of the reaction and thus affects also the yield and the purity of the compounds obtained.

SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide novel cytostatic compounds which have an increased and broad species cytostatic action.

It is a further object of the invention to provide such compounds which can be administered orally and have a low acute and chronic toxicity.

It is a still further object of the invention to provide improved processes for condensing the mucohalogenoacid to the lactone and converting the latter by further processing to a aroyl-substituted halogenoacrylic acid. It is in particular an object of the invention in this connectiori to provide processes in both instances which avoid decomposition of the starting products or the final reaction products and result in improved yields and purity and have a high reproducibility.

These objects are met by a compound of the formula X in the last residue being chlorine or bromine.

An example of a lactone is 'y-4-n-butoxyphenyl-a,/8- dibromQ-N- -crotOnic acid lactone. An example of the hydrolysis product is 18-4-n-pentyloxybenzoyl-fl-bromoacrylic acid.

The lactone-type compound is formed by condensing a mucohalo acid of the formula X X (II) wherein X is bromine or chlorine, in the presence of substantially anhydrous zinc chloride or a mixture of anhydrous zinc chloride with phosphorus pentoxide, preferably at a temperature between 60 and C.

The halogenoacrylic acid which is the hydrolysis product of the lactone may be formed by subjecting the lactone to a reaction with water and an organic water-miscible solvent in the presence of zinc oxide and at the boiling temperature of the reaction mixture.

DESCRIPTION OF THE PREFERRED EMBODIMENTS (I) The lactones The crotonic acid lactones of the invention have been submitted to broad selection tests regarding their antineoplastic action on different transplantable tumors in the case of oral administration. More detailed tests were then carried out, as follows, with 'y-4-n-butoxyphenyl-a 6- dibromo-A -crotonic acid lactone. These tests showed the following results:

Acute toxicity: It was determined that the LD in mice was 16 g./kg. of body weight in the case of oral administration. This compared with 320 mg./l g. in the The activity of the compound under investigation was expressed by a fraction in which the numerator gives in percentage the average size of the tumor in a test group compared with the average size of the tumor in an untreated control group, which latter was taken as 100%.

case of the -4-methoxybenzoyl-B-bromoacrylic acid of 5 The denominator shows, in percentage, the average surthe prior art (Pat. No. 3,105,850). vival time of the treated animals compared with the aver- Chronic toxicity: The chronic toxicity was determined age survival time of an untreated control group, which by tests with groups of males and 10 females each was taken as 100%. The test results show a substantially on rats of the Wistar species over a period of 3 months. 10 therapeutic cancerostatic action of the investigated com- During this period, the animals were given doses of 50, pound in the case of sarcoma S 180, adenocarcinoma of 100 and 200 mg./kg. in the different groups, per day, and the mammary gland HK, of the Ehrlich-ascitescarcinoma by oral administration in the form of suspension in water. ATE and the Yoshida-ascitessarcoma Y.

From the histological, biochemical and hematological in- The lactones of the present invention are preferably vestigation or determination it was found that the dose made by condensing a mucohalo acid of the formula of 50 org/kg. daily per os did not result in any undesirable side etfects nor in any elfect on the food intake, CHO (E COOH the growth, or the blood composition. There was in par- X X (H) ticular no macroscopic or microscopic injury detectable wherein X is bromine or chlorine with a substituted to the inner organs (liver, spleen and kidneys) and no benzene of the formula action on the activity of the glutamate-pyruvate-transaminase or of the residual nitrogen or the blood proteins.

The higher dosis (100 and 200 mg./kg. daily per os) resulted in a moderate microscopically detectable liver (In) and spleen injury when administered under the same conditions, and in the case of females caused a slight elfect wherein 1, 2 and s have the Same meaning as given on the blood proteins in the direction of hyperproteinemia. above in the case of Formula I. This condensation is High cytostatic action of the butoxyphenyl-substituted preferably carried out in the presence of anhydrous zinc crotone lactone defined above was found to exist in the chloride of a mixture of anhydrous Zinc chlolide with case of certain transplantable tumors, not only in the form p phorus pentoxide at a temperature between 60 and of an inhibition of the tumor growth, but primarily in the 85 C. and preferably between 75 and 80 C. The subform of a significant prolongation of the survival tim of stantially anhydrous zinc chloride should contain at most the treated animals. To specifically determine these acwater and is used in an amount by weight half of tions, the following seven types of transplantable tumors that or equal to that of the mucohalogenic acid of For were implanted in the animals and subjected to th i mula II. If desired, the zinc chloride may be mixed with vestigation: 5 to 20% phosphorus pentoxide. The use of these agents S 180 Cro ckelasar c0 ma in the indicated condensation reaction is substantially HK adenocarcinoma of the mammary g1 an d superior to the plrior art reactions which were carried out ATE Ehflich ascitescarcinoma with polyphosp oric acid. The comparatively cumber- S 37 ascites sarcoma some requirement to have available a large amount of the Kr z cancerous ascitemarcoma polyphosphorus acid is avoided. The volume of the reac- 6C3HED Gardneplymphosarcoma tion mixture thus becomes smaller and the yield increases y yoshida ascitessarcoma in rats and the reaction 1s more easily reproducible. The starting products and the reaction product are subject to a smaller The adm1n1stm;t111 t0 the 3111111218 Was efiected, 111 the risk of decomposition. In addition, it is possible to form 2 0f l tumors 180 and g ing certain derivatives, for instance, 'y-4-hydroxy-2-methoxywith the third ay afterfhe transplalltatlbn and for a phenylnx,fi-dibromocrotordc acid lactone, which could not Period of 12 y Once y- In e C se f ascites tumors be made when using polyphosphoric acid as the condensa- (ATE, S 37, Kr 2, 6 C HED, and Y), the administration ti agent, was effected once daily for S days, starting with the sec- The optimum time of reaction depends on the char- Ond y the ifanslflantatlon- A r completion of the actor of the substituted benzene of Formula III. It can gggg a il l g gi ll fst z'gs tg goz 21ft? lpyrzfitiarrsdl tuImors gas vary between 15 minutes and hours, the prolongation of test on of 10 1 h p a S- 1 not or the react on does not ordinarily have a perceptible eifect 8 P anlma t e SufVlVal m 0f the 318 on the yield in view of the non-deleterious nature of the was noted. condensation agent.

In the second test groups nvolving ascites tumors The isolation of the lactones from the reaction mixture 6C HED and Y, only the survival time in a IO-auimal is very simple. It can, for instance, be effected by the group was noted. The average size of the tumors and the distribution of the product between chloroform and average survival time were then compared with the averwater, evaporation of the organic portion up to dryness, age1 va lIuhes gliiitained in a parallel group of untreated aniand purification of the residue by recrystallization from a inlaeit ans eiyaielreiietgs 3 1cm staltistically calculated by the suitable solvent or by chromatography over a silica gel 1 t bl a e resu ts are indicated in the folcolumn and subsequent recrystallization of the product owing a e. obtained by means of an organic solvent.

Dosage,

per diem Total S 180 HK ATE S 37 K1 2 fiCsHED Y ion 500 /222 200.-.. 2,400 89/115 88/103 Jog/100 I103 m0 300.--- 1,500 54/111 -I --IIIIIIIIIIIIIIIIIIIII:

The following examples will illustrate the making of the lactones without any intention of limitation.

EXAMPLE I 'y-4-n-hexyloxyphenyl-a, S-dibromo-A--crotonic acid lactone A mixture of 25.8 g. of mucobromic acid, 13.6 g. anhydrous zinc chloride, 1.36 g. phosphorus pentoxide and 17.8 g. n-hexylphenylether is heated upon exclusion of the humidity of the air and upon stirring for 5 hours in a bath maintained at 7580 C. After cooling down of the molten mixture to about 40 C., 125 ml. of chloroform and 50 ml. of water having a temperature of about 30 C. are added, and the resulting mixture is subjected to thorough stirring. The chloroform layer is separated and subjected to repeated shaking with water and drying over anhydrous sodium sulfate. The solvent is removed by distillation after filtration. There are obtained 36.1 g. (86%) of a viscous crude product which furnishes the recrystallization material (methanol) after chromatography over a silica gel column (using benzene as eluent) in a yield of 34.4 g. (82%) and has a melting-point of 5658 C.

EXAMPLE II -4-hydroxy-2-methoxyphenyl-a,B-dibromo-A-crotonic acid lactone A mixture of 25.8 g. mucobromic acid, 12.4 g. resorcinolmonomethylether and 13.6 g. anhydrous zinc chloride are heated upon exclusion of air humidity and stirring for 3 hours in a bath that is maintained at 75-80 C. After treating the reaction mixture as in the preceding example but without chromatography, a crude product is obtained in a yield of 28.7 g. (79%). After recrystallization from methanol, the pure material is found to have a melting-point of between 155-156 C.

EXAMPLE III -4-n-pentyloxyphenyl-a,fl-dichloro-A="-crotonic acid lactone By using 16.9 g. mucochloric acid, 16.4 g. n-pentylphenylether, 13.6 g. anhydrous zinc chloride and 1.36 g. phosphorus pentoxide in a procedure as indicated in the preceding examples, there is obtained the product as stated in the heading of this example, at a yield of 28.6 g. (91%). Its melting-point after recrystallization from methanol is 58-59 C.

EXAMPLES IV-X In the same manner, using exactly the same mol relationship of the several reaction components and the same amounts of anhydrous zinc chloride and phosphorus pentoxide, yields from 80-95% of the following compositions were obtained: (4) 'y-4-ethoxyphenyl-a,fi-dibromo-A"-crotonic acid lactone, M.P. 96-97 C. (methanol) (5) 'y-4-propyloxyphenyl-u,;8-dibromo-N -crotonic acid lactone, M.P. 57-58 C. (methanol) (6) 'y-4-n-butoxyphenyl-u,/3-dibromo-A-"-crotonic acid lactone, M.P. 74-75 C. (methanol) (7) -4-n-pentyloxyphenyl-a,fi-dibromo-A -crotonic acid lactone, M.P. 82-84 C. (methanol) (8) 'y-2,4-dimethoxyphenyl-a,fi-dibromo-N -crotonic acid lactone, M.P. 1l2-114 C. (methanol) (9) -2,3,4-trimethoxyphenyl-a,fi-dibromo-A -crotonic acid lactone, M.P. 117119 C. (methanol) (10) y-2,4,6-trimethoxyphenyl-a,fi-dibromo-u' crotonic acid lactone, M.P. l76l78 C. (methanol) (II) The hydrolysis products The lactones previously described can easily be hydrolyzed to form halogenoacrylic acids of the following wherein X is chlorine or bromine, R is hydrogen, or alkoxy having 1 to 6 carbon atoms, R is hydrogen or hydroxy or alkoxy having 1 to 6 carbon atoms, and R is alkoxy having 1 to 6 carbon atoms, with the proviso that when R and R are both hydrogen, R shall be alkoxy having 2 to 6 carbon atoms.

The halogenoacrylic acids defined have been found to possess a therapeutic action on animals with transplantable tumors in the case of parenteral administration. This action was With undesired side effects.

It was furthermore found that, for instance, the B-4-npentyloxybenzoyl-p-bromoacrylic acid was effective therapeutically also after peroral administration. This is a great advantage over the previously known fi-4-methoxybenzoyl-fl-bromoacrylic acid, which could be used only parenterally in the form of its sodium salts.

The halogenoacrylic acids can be obtained by hydrolysis of the previously described crotonic acid lactones of the formula:

C O Rg wherein X, R R and R have the same meaning as in Formula IV, with a mixture of Water and a Water-miscible solvent, preferably dioxane, in the presence of zinc oxide and at the boiling temperature of the reaction mixture.

The amount of zinc oxide used for the hydrolysis is preferably from 1 to 4 mols relative to 1 mol of the lactone used as starting product.

Under the stated conditions, the hydrolysis proceeds with very good yields, in some cases almost quantitatively. The zinc salt of the ,8-aroyl-fl-halogenoacrylic acid is substantially more stable compared, for instance, with the magnesium or sodium salt, and is not subject to decomposition during the reaction. The hydrogen halide that is formed during the hydrolysis of the lactone is bound in the form of the corresponding zinc halide. The use of zinc oxide thus permits the production of the desired acids with a high yield, usually above 90%, and at an almost analytical degree of purity, particularly be cause of the high stability of the zinc salt formed and the small possibility of deleterious action on the salt.

The fl-aroyl-halogenoacrylic acids of the Formula IV can, for instance, be isolated by subjecting the reaction mixture after completion of the hydrolysis to evaporation to dryness under reduced pressure, dissolving the residue in water upon addition of sodium bicarbonate, whereupon the desired acid is liberated from the solution of its sodium salt by acidifying it with hydrogen chloride. It is also possible to proceed in the manner that the residue is distributed between dilute hydrochloric acid and chloroform, whereupon the chloroform extract is evaporated to dryness and the residue is purified by crystallization.

EXAMPLE XI A solution of 22.2 g. ,B-4-ethoxybenzoyl-a, 8-dibromo- N -crotonic acid lactone in 20 ml. dioxane is added dropwise to a boiling mixture of 240 ml. water and dioxane (in the ratio 1:1) and 5 g. zinc oxide. The addition is effected Within 20 minutes and at a speed sufficient to keep the reaction mixture continuously at the boilingpoint. After permitting the mixture to boil for another minutes, the solvent is removed from the mixture by distillation at 40 C. and 14 torr and the residue is extracted for one hour with a warm solution (30-35 C.) of 24 g. sodium bicarbonate in 240 ml. water. The solution obtained of the ,8-4-ethoxybenzoyl-fi-bromoacrylic acid sodium salt is acidified after filtration with cone. sulfuric acid and upon vigorous stirring to obtain a pH between 2 and 3. The acid that separates out is removed by suction after cooling to 5 C. and is dried in air at room temperature. The yield after recrystallization from ben- 7 zene is 17.2 g. (94%), melting-point between 149-150 C general reaction medium, the following compositions were obtained in a yield between 80-90% (12) ,B-4-n-propoxybenzoyl-B-bromoacrylic acid, M.P.

118119 C. (benzene) (13) 3-4-n-butoxybenzoyl-p-brornoacrylic acid, M.P.

122-123 C. (benzene-hexane) (14) fi-4n-pentyloxybenzoyl-fi-bromoacrylic acid, M.P.

103104 C. (benzene-heptane) (15) ,8-4-hexyloxybenzoyl-fi-bromoacrylic acid, M.P.

98-99 C. (benzene-hexane) 16) ,B-4-n-pentyloxybenzoyl-[i-chromoacrylic acid, M.P.

94-95 C. (benzene) (17) 3-2,4-dimethoxybenzoyl-fi-bromoacrylic acid, M.P.

133-135 C. (benzene) (18) -2,3,4-trimethoxybenzoyl-fi-bromoacrylic acid,

M.P. 120121 C. (benzene) (19) a -2,4,6-trimethoxybenzoyl-fi-bromoacrylic acid,

M.P. 156157 C. (benzene) (20) ,3-2,3,4-trimethoxybenzoyl-B-chloroacrylic acid,

M.P. 114-115" C. (methanol) Without further analysis, the foregoing will so fully reveal the gist of the present invention that others can by applying current knowledge readily adapt it for various applications without omitting features that, from the 5 standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this invention and, therefore, such adaptations should and are intended to be comprehended within the meaning and range of equivalence of the following claim.

Letters Patent is set forth in the appended claim.

We claim: 1. 8-4-n-pentyloxybenzoyl-fl-bromoacrylic acid.

References Cited UNITED STATES PATENTS 3,105,850 10/1963 Semonsky 280521 R OTHER REFERENCES Semonsky, Chem. Abst. 59 3822c (1963).

Arora et a1., Canad. J. Chem. 45 1), 67-73 (1967).

CA. 57 14986 (1962), Semonsky et a1. (II).

LORRAINE A. WEINBERGER, Primary Examiner J. F. TERAPANE, Assistant Examiner US. Cl. X.R.

What is claimed as new and desired to be protected by 

